Naphthyridine derivatives

ABSTRACT

The present invention provides a novel naphthyridine derivative that is effective for relieving pain, less toxic, and also is effective for treating diabetic neuropathy, the derivative being represented by the general formula (1):  
                 
 
     wherein R 1 , R 2 , R 3  and R 4  are as described in the description.

TECHNICAL FIELD

[0001] The present invention relates to novel naphthyridine derivatives.

BACKGROUND ART

[0002] The inventor previously found novel naphthyridine derivativesthat have an analgesic effect, and accomplished an invention relating tothe derivatives [PCT/JP98/03045 (international publication No. WO99/02527A1)]. However, in continued research, the inventor found thatthe derivatives show little effect in the case of treating diseases,such as diabetic neuropathy, in which the nervous system is damaged,barely achieving the desired analgesic effect, and furthermore, theinventor recognized that administration of the derivatives may causeside effects, such as hypertrophy of the thyroid gland, etc.

DISCLOSURE OF THE INVENTION

[0003] An object of the present invention is to provide novelnaphthyridine derivatives that exhibit superior pharmacologicalproperties to the above-mentioned derivatives previously developed bythe inventor and that are more useful in the pharmaceutical field.

[0004] To achieve the above-mentioned object, the inventor conductedintensive research and found that the new derivatives represented bygeneral formula (1) below can achieve the object and accomplished thepresent invention.

[0005] The invention provides a novel naphthyridine derivativerepresented by the following general formula (1):

[0006] wherein

[0007] R¹ represents a hydrogen atom or a lower alkyl group;

[0008] R² represents a hydrogen atom, a lower alkyl group, a cycloalkylgroup, phenyl group, or a phenyl-lower alkyl group optionally having 1to 3 lower alkoxy groups on the phenyl ring;

[0009] R³ and R⁴ each independently represent the group —Y—O—Z—R⁵(wherein Y is a lower alkylene group, Z is a single bond or a loweralkylene group, and R⁵ is phenyl group optionally having 1 to 3substituents selected from the group consisting of halogen atoms, loweralkoxy groups, lower alkyl groups, halogen-substituted lower alkylgroups, methylenedioxy group, hydroxyl group, 2,2-di(loweralkoxycarbonyl)ethyl groups and 2,2-di(lower alkoxycarbonyl)vinylgroups; or one of R³ and R⁴ is the group —Y—O—Z—R⁵ (wherein Y, Z and R⁵are as defined above) and the other is a lower alkyl group, phenylgroup, or a phenyl-lower alkyl group;

[0010] with the proviso that the case where R² is a phenyl-lower alkylgroup optionally having 1 to 3 lower alkoxy groups on the phenyl ringand at least one of R³ and R⁴ is a benzyloxy-lower alkyl group having 1to 3 lower alkoxy groups on the benzene ring is excluded.

[0011] The invention further provides a pharmaceutical composition thatcomprises the above naphthyridine derivative and a pharmaceuticallyacceptable carrier; in particular, a pharmaceutical composition thatserves as an analgesic, a pharmaceutical composition that serves as adiabetic neuropathy treatment agent, and/or a pharmaceutical compositionthat serves as an adenosine enhancement agent.

[0012] Furthermore, the present invention provides a method forrelieving pain in a patient, a method for treating diabetic neuropathyin a patient, or a method for enhancing adenosine in a patient, whichcomprises administrating an effective amount of the above-mentionednaphthyridine derivative to the patient in need of such treatment.

[0013] Hereafter, the derivative of the present invention is describedin detail.

[0014] Specific examples of groups in the above-mentioned generalformula (1) and other general formulae in the specification arementioned below. In the specification, the word “lower” that is used todescribe carbon-containing groups means “having 1 to 6 carbon atoms”.

[0015] Examples of lower alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and like straight-or branched-chain alkyl groups having 1 to 6 carbon atoms.

[0016] Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and like cycloalkylgroups having 3 to 8 carbon atoms.

[0017] Examples of lower alkoxy groups include methoxy, ethoxy, propoxy,isopropoxy, butoxy, pentyloxy, hexyloxy and like straight- orbranched-chain alkoxy groups having 1 to 6 carbon atoms.

[0018] Examples of lower alkylene groups include methylene, ethylene,ethylidene, trimethylene, tetramethylene, pentamethylene, hexamethyleneand like straight- or branched-chain alkylene groups having 1 to 6carbon atoms.

[0019] Examples of halogen atoms include fluorine, chlorine, bromine,and iodine.

[0020] Examples of halogen-substituted lower alkyl groups includeperhalogeno-(C₁₋₆-alkyl) groups having halogen atoms selected from thegroup consisting of fluorine, chlorine, bromine and iodine, assubstituents, and in particular, perfluoro-(C₁₋₆-alkyl) groups. Specificexamples thereof are trifluoromethyl, pentafluoroethyl,heptafluoropropyl, nonafluorobutyl, undecafluoropentyl,tridecafluorohexyl groups, etc.

[0021] Examples of 2,2-di(lower alkoxy-carbonyl)ethyl groups include2,2-dimethoxycarbonylethyl, 2,2-diethoxycarbonylethyl,2,2-dipropoxycarbonylethyl, 2,2-dibutoxycarbonylethyl,2,2-dipentyloxycarbonylethyl, 2,2-dihexyloxycarbonylethyl and like2,2-di(C₁₋₆-alkoxy-carbonyl)ethyl groups.

[0022] Examples of 2,2-di(lower alkoxy-carbonyl)vinyl groups include2,2-dimethoxycarbonylvinyl, 2,2-diethoxycarbonylvinyl,2,2-dipropoxycarbonylvinyl, 2,2-dibutoxycarbonylvinyl,2,2-dipentyloxycarbonylvinyl, 2,2-dihexyloxycarbonylvinyl and like2,2-di(C₁₋₆-alkoxy-carbonyl)vinyl groups.

[0023] Examples of phenyl-lower alkyl groups include benzyl,1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,5-phenylpentyl, 6-phenylhexyl and like phenyl-C₁₋₆-alkyl groups.

[0024] Examples of phenyl-lower alkyl groups optionally having 1 to 3lower alkoxy groups on the phenyl ring include, in addition to theabove-mentioned phenyl-lower alkyl groups, 2-methoxybenzyl,3-methoxybenzyl, 4-methoxybenzyl, 4-ethoxybenzyl, 4-propoxybenzyl,4-butoxybenzyl, 4-pentyloxybenzyl, 4-hexyloxybenzyl,2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl,2,6-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl,2,3,4-trimethoxybenzyl, 2,3,5-trimethoxybenzyl, 2,4,5-trimethoxybenzyl,3,4,5-trimethoxybenzyl, 3,4,5-triethoxybenzyl, 1-(4-methoxyphenyl)ethyl,2-(4-methoxyphenyl)ethyl, 3-(4-methoxyphenyl)propyl,4-(4-methoxyphenyl)butyl, 5-(4-methoxyphenyl)pentyl,6-(4-methoxyphenyl)hexyl, 1-(3,4,5-trimethoxyphenyl)ethyl,2-(3,4,5-trimethoxyphenyl)ethyl, 3-(3,4,5-trimethoxyphenyl)propyl,4-(3,4,5-trimethoxyphenyl)butyl, 5-(3,4,5-trimethoxyphenyl)pentyl,6-(3,4,5-trimethoxyphenyl)hexyl and like phenyl-C₁₋₆-alkyl groupsoptionally having 1 to 3 C₁₋₆-alkoxy groups on the phenyl ring.

[0025] Examples of phenyl groups optionally having 1 to 3 substituentsselected from the group consisting of halogen atoms, lower alkoxygroups, lower alkyl groups, halogen-substituted lower alkyl groups,methylenedioxy group, hydroxyl group, 2,2-di(lower alkoxy-carbonyl)ethylgroups and 2,2-di(lower alkoxy-carbonyl)vinyl groups are, in addition tounsubstituted phenyl group, the following:

[0026] 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-bromophenyl, 4-iodophenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl,4-pentyloxyphenyl, 4-hexyloxyphenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,4-pentafluoroethylphenyl, 4-heptafluoropropylphenyl,4-nonafluorobutylphenyl, 4-undecafluoropentylphenyl,4-tridecafluorohexylphenyl, 2,3-methylenedioxyphenyl,3,4-methylenedioxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, 2-(2,2-dimethoxycarbonylethyl)phenyl,3-(2,2-dimethoxycarbonylethyl)phenyl,4-(2,2-dimethoxycarbonylethyl)phenyl,4-(2,2-diethoxycarbonylethyl)phenyl,4-(2,2-dipropoxycarbonylethyl)phenyl,4-(2,2-dibutoxycarbonylethyl)phenyl,4-(2,2-dipentyloxycarbonylethyl)phenyl,4-(2,2-dihexyloxycarbonylethyl)phenyl,2-(2,2-dimethoxycarbonylvinyl)phenyl,3-(2,2-dimethoxycarbonylvinyl)phenyl,4-(2,2-dimethoxycarbonylvinyl)phenyl,4-(2,2-diethoxycarbonylvinyl)phenyl,4-(2,2-dipropoxycarbonylvinyl)phenyl,4-(2,2-dibutoxycarbonylvinyl)phenyl,4-(2,2-dipentyloxycarbonylvinyl)phenyl,4-(2,2-dihexyloxycarbonylvinyl)phenyl, 2,3-dichlorophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl,2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl,2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl,2,4,6-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl,2,4,5-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3-dimethylphenyl,2,4-dimethylphenyl; 2,5-dimethylphenyl, 2,6-dimethylphenyl,3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl,2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,4,5-trimethylphenyl,3,4,5-trimethylphenyl, 2,3-bis(trifluoromethyl)phenyl,2,4-bis(trifluoromethyl)phenyl, 2,5-bis(trifluoromethyl)phenyl,2,6-bis(trifluoromethyl)phenyl, 3,4-bis(trifluoromethyl)phenyl;3,5-bis(trifluoromethyl)phenyl, 2,4,6-tris(trifluoromethyl)phenyl,2,3,4-tris(trifluoromethyl)phenyl; 2,3,5-tris(trifluoromethyl)phenyl;2,4,5-tris(trifluoromethyl)phenyl; 3,4,5-tris(trifluoromethyl)phenyl;2,3-dihydroxyphenyl; 2,4-dihydroxyphenyl; 2,5-dihydroxyphenyl;2,6-dihydroxyphenyl; 3,4-dihydroxyphenyl; 3,5-dihydroxyphenyl;2,4,6-trihydroxyphenyl; 2,3,4-trihydroxyphenyl; 2,3,5-trihydroxyphenyl;2,4,5-trihydroxyphenyl; 3,4,5-trihydroxyphenyl;2,4-bis(2,2-dipentyloxycarbonylethyl)phenyl; 3,5-bis(2,2-dipentyloxycarbonylethyl)phenyl; 2,5-bis(2,2-dipentyloxy carbonylethyl)phenyl;2,6-bis(2,2-dipentyloxy carbonylethyl)phenyl; 2,4,6-tris(2,2-dipentyloxycarbonylethyl)phenyl; 2,4-bis(2,2-dipentyloxy carbonylvinyl)phenyl;3,5-bis(2,2-dipentyloxy carbonylvinyl)phenyl; 2,5-bis(2,2-dipentyloxycarbonylvinyl)phenyl; 2,6-bis(2,2-dipentyloxy carbonylvinyl)phenyl;2,4,6-tris(2,2-dipentyloxy carbonylvinyl)phenyl;3,4-methylenedioxy-5-methoxyphenyl; 2,3-methylenedioxy-4-methoxyphenyl;2,3-methylenedioxy-5-methoxyphenyl; 5-hydroxy-3,4-methylenedioxyphenyl;5-hydroxy-2,3-methylenedioxyphenyl; 4-hydroxy-2,3-methylenedioxyphenyl;3-hydroxy-4,5-dimethoxyphenyl; 4-hydroxy-3,5-dimethoxyphenyl;4-hydroxy-2,6-dimethoxyphenyl; 3,5-dihydroxy-4-methoxyphenyl;2,6-dihydroxy-4-methoxyphenyl; 4-hydroxy-3,5-dimethylphenyl;4-methoxy-3,5-dimethylphenyl; 4-hydroxy-3,5-di-t-butylphenyl;4-methoxy-3,5-di-t-butylphenyl; 2-chloro-4-methoxyphenyl;4-chloro-2-methoxyphenyl; 2-chloro-4-methylphenyl;4-chloro-2-methylphenyl; 2-chloro-4-trifluoromethylphenyl;4-chloro-2-trifluoromethylphenyl; 2-chloro-4,5-methylenedioxyphenyl;5-chloro-2,3-methylenedioxyphenyl; 2-chloro-4-hydroxyphenyl;4-chloro-2-hydroxyphenyl; 2-chloro-4-(2,2-dimethoxycarbonylethyl)phenyl;4-chloro-2-(2,2-dimethoxycarbonylethyl)phenyl;2-chloro-4-(2,2-dimethoxycarbonylvinyl)phenyl;4-chloro-2-(2,2-dimethoxycarbonylvinyl)phenyl; 3-methoxy-4-methylphenyl;4-methoxy-3-methylphenyl; 3-methoxy-4-trifluoromethylphenyl;4-methoxy-3-trifluoromethylphenyl; 3-hydroxy-4-methoxyphenyl;4-hydroxy-3-methoxyphenyl;4-(2,2-dimethoxycarbonylethyl)-2-methoxyphenyl;2-(2,2-dimethoxycarbonylethyl)-4-methoxyphenyl;4-(2,2-dimethoxycarbonylvinyl)-2-methoxyphenyl;2-(2,2-dimethoxycarbonylvinyl)-4-methoxyphenyl;3-methyl-4-trifluoromethylphenyl; 4-methyl-3-trifluoromethylphenyl;4-methyl-2,3-methylenedioxyphenyl; 2-methyl-3,4-methylenedioxyphenyl;3-hydroxy-4-methylphenyl; 4-hydroxy-3-methylphenyl;4-(2,2-dimethoxycarbonylethyl)-2-methylphenyl;2-(2,2-dimethoxycarbonylethyl)-4-methylphenyl;4-(2,2-dimethoxycarbonylvinyl)-2-methylphenyl;2-(2,2-dimethoxycarbonylvinyl)-4-methylphenyl;2,3-methylenedioxy-4-trifluoromethylphenyl;3,4-methylenedioxy-5-trifluoromethylphenyl;3-hydroxy-4-trifluoromethylphenyl; 4-hydroxy-3-trifluoromethylphenyl,4-(2,2-dimethoxycarbonylethyl)-2-trifluoromethylpheny,2-(2,2-dimethoxycarbonylethyl)-4-trifluoromethylphenyl,4-(2,2-dimethoxycarbonylvinyl)-2-trifluoromethylphenyl,2-(2,2-dimethoxycarbonylvinyl)-4-trifluoromethylphenyl,2,3-methylenedioxy-5-(2,2-dimethoxycarbonylethyl)phenyl,2,3-methylenedioxy-5-(2,2-dimethoxycarbonylvinyl)phenyl,4-(2,2-dimethoxycarbonylethyl)-2-hydroxyphenyl,2-(2,2-dimethoxycarbonylethyl)-4-hydroxyphenyl,4-(2,2-dimethoxycarbonylvinyl)-2-hydroxyphenyl,2-(2,2-dimethoxycarbonylvinyl)-4-hydroxyphenyl,4-(2,2-dimethoxycarbonylethyl)-2-(2,2-dimethoxycarbonylvinyl)phenyl,2-(2,2-dimethoxycarbonylethyl)-4-(2,2-dimethoxycarbonylvinyl)phenylgroup, etc.

[0027] Among the naphthyridine derivatives of the invention, the groupcomprising the compounds defined in (1)-(6) below is preferable.Hereinafter, this group may be referred to as group A compounds of theinvention.

[0028] (1) A naphthyridine derivative represented by the formula (1)wherein one of R³ and R⁴ is a lower alkyl group.

[0029] (2) A naphthyridine derivative according to (1), wherein R¹ is ahydrogen atom.

[0030] (3) A naphthyridine derivative according to (2), wherein R² is aphenyl-lower alkyl group optionally having 1 to 3 lower alkoxy groups onthe phenyl ring.

[0031] (4) A naphthyridine derivative according to (3), wherein Z is asingle bond.

[0032] (5) A naphthyridine derivative according to (4), wherein R⁵ isphenyl having 1 to 3 lower alkoxy groups as substituents.

[0033] (6) A naphthyridine derivative according to (5), wherein R² isbenzyl optionally having 1 to 3 lower alkoxy groups on the phenyl ring.

[0034] Among the above-described group A compounds of the invention,compounds of (4)-(6) exhibit especially excellent pharmacologicalactivity.

[0035] Among the naphthyridine derivatives of the present invention,another preferable group include the compounds defined in (7)-(9)mentioned below. Hereafter, this group may be called group B compoundsof the invention.

[0036] (7) A naphthyridine derivative represented by the formula (1),wherein one of R³ and R⁴ is a lower alkyl group and Z is a single bond.

[0037] (8) A naphthyridine derivative according to (7), wherein R⁵ isphenyl having three lower alkoxy groups as substituents.

[0038] (9) A naphthyridine derivative according to (7), wherein R⁵ is3,4,5-tri-lower alkoxy-phenyl group.

[0039] Each compound belonging to group B compounds of the inventionexhibits excellent pharmacological activity with minimal side effects.Among these, the compounds defined in (8) and (9) have more potentpharmacological activity.

[0040] The specific compounds encompassed in the preferablenaphthyridine derivatives of the present invention in terms of favorablepharmacological activity and side effects are listed in (10) below:

[0041] (10)1-(3,4,5-trimethoxybenzyl)-3-[methyl-2-(3,4,5-trimethoxyphenoxy)ethylsulfonium]-1,8-naphthyridine-2(1H)-one-4-olate,1-benzyl-3-[ethyl-3-(3,4,5-trimethoxyphenoxy)propylsulfonium]-1,8-naphthyridine-2(1H)-one-4-olate,1-methyl-3-[methyl-2-(3,4,5-trimethoxyphenoxy)ethylsulfonium]-1,8-naphthyridine-2(1H)-one-4-olate,1-benzyl-3-[methyl-3-(3,4,5-trimethoxyphenoxy)propylsulfonium]-1,8-naphthyridine-2(1H)-one-4-olate,and1-(4-methoxybenzyl)-3-[methyl-3-(3,4,5-trimethoxyphenoxy)propylsulfonium]-1,8-naphthyridine-2(1H)-one-4-olate.

[0042] Among these,1-benzyl-3-[methyl-3-(3,4,5-trimethoxyphenoxy)propylsulfonium]-1,8-naphthyridine-2(1H)-one-4-olateis the most preferable.

[0043] The naphthyridine derivatives of the invention can be produced byvarious processes. Exemplary processes are shown below with reference toreaction schemes.

[0044] [wherein R¹, R², R³ and R⁴ are as defined above, and Phrepresents phenyl.]

[0045] In Reaction Scheme-1, compound (2) is reacted with iodobenzenediacetate in the presence of an alkali, giving compound (3). Water issuitably used as a solvent in the reaction. Useful alkalis include, forexample, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogen carbonate. The alkali and iodobenzenediacetate are each preferably used in an equimolar amount to slightexcess relative to the starting compound. The reaction is carried out ata temperature from about 0° C. to about room temperature and iscompleted in about 1 to 10 hours.

[0046] Subsequently, the resulting compound (3) is reacted withthioether derivative (4), giving compound (1) of the invention. Thereaction may be carried out using a lower alcohol, such as methanol,ethanol, trifluoroethanol or the like as a solvent and adding a suitableamount of an acid catalyst, such as p-toluenesulfonic acid, acetic acidor the like. Thioether derivative (4) is preferably used in an amount ofabout 1 to 10 moles per mole of compound (3). The acid catalyst ispreferably used in an amount of 0.005 to 0.5 moles per mole of compound(3). The reaction is carried out at a temperature in the range from roomtemperature to reflux temperature and is completed in about 10 minutesto 24 hours.

[0047] In the above process, compound (2) used as a starting compoundcan be produced, for example, by following the steps below.

[0048] [wherein R¹ and R² are as defined above, and R represents a loweralkyl group.]

[0049] The acetylation reaction of compound (5) shown in ReactionScheme-2 is conducted by heating compound (5) in an excess of aceticanhydride at 100° C. to a reflux temperature for 10 to 100 hours.Cyclization of acetamide derivative (6) obtained by this reaction iscarried out by heating acetamide derivative (6) in an aromatichydrocarbon inert solvent, such as toluene, xylene, mesitylene, cumene,and cymene, in the presence of a base such as potassium-t-butoxide orsodium ethoxide. The preferable amount of base is 1 to 5 times of molesper mole of starting compound. The heating temperature is in the rangefrom about 100° C. to reflux temperature, and heating time is in therange from about 0.5 to 5 hours.

[0050] Compound (1) of the invention obtained by the above process isconsidered to have the resonance structures as shown below. Therefore,the compound of the present invention can be represented by any one ofthe following structural formulae.

[0051] The compounds of the invention can be easily isolated andpurified by conventional separation and purification methods. Thesemethods include those generally employed, such as adsorptionchromatography, preparative thin-layer chromatography, recrystallizationand solvent extraction, etc.

[0052] Some of the compounds of the invention are optical isomers withsulfur and/or carbon as an asymmetric center. The present inventionincludes both racemates, which are a mixture of such optical isomers,and individual optically active forms, which are optical isomers. Theoptically active isomers can be isolated by conventional methods, suchas methods using known optical resolving agents.

[0053] The compound represented by formula (1) of the invention hasexcellent analgesic effects and is useful as a medicine, particularly asan analgesic. In particular, the compound is effective in relievingpostoperative pain and cancer pain. The compound of the invention isalso useful as a diabetic neuropathy treatment agent or an adenosineenhancement agent. The compound of the present invention ischaracterized in that it exhibits minimal side effects, such ashypertrophy of the thyroid gland, than the naphthyridine derivative thathas been previously developed by the inventor.

[0054] The present invention provides a pharmaceutical compositioncomprising the compound of the invention represented by theabove-mentioned general formula (1) as an active ingredient. Thispharmaceutical composition is formed into general pharmaceuticalpreparations using the compound of the invention and pharmaceuticallyacceptable carriers and then administered.

[0055] Examples of pharmaceutically acceptable carriers for use in thepharmaceutical compositions of the invention are conventional diluentsor excipients, such as fillers, extenders, binders, humectants,disintegrators, surfactants, lubricants and the like, which are suitablyselected and used according to the desired unit dosage form.

[0056] A suitable unit dosage form can be selected from a variety offorms according to the therapeutic purpose. Typical examples aretablets, pills, powders, solutions, suspensions, emulsions, granules,capsules, suppositories, injections (solutions, suspensions, etc.),ointments and the like.

[0057] In producing tablets, usable as the above pharmaceuticallyacceptable carriers are excipients, such as lactose, sucrose, sodiumchloride, glucose, urea, starch, calcium carbonate, kaolin, crystallinecellulose, silicic acid and potassium phosphate; binders such as water,ethanol, propanol, simple syrup, glucose syrup, starch solution, gelatinsolution, carboxymethyl cellulose, hydroxypropyl cellulose, methylcellulose and polyvinyl pyrrolidone; disintegrators such as sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose,low-substituted hydroxypropyl cellulose, dry starch, sodium alginate,agar powder, laminaran powder, sodium hydrogen-carbonate and calciumcarbonate; surfactants such as polyoxyethylene sorbitan fatty acidesters, sodium lauryl sulfate and stearic acid monoglyceride;disintegration inhibitors such as sucrose, stearin, cacao butter andhydrogenated oil; absorption promoters such as quaternary ammonium basesand sodium lauryl sulfate; humectants such as glycerin and starch;adsorbents such as starch, lactose, kaolin, bentonite and colloidalsilicic acid; and lubricants such as purified talc, salts of stearicacid, boric acid powder and polyethylene glycol. If necessary, thetablets can be made into coated tablets, such as sugar-coated tablets,gelatin-coated tablets, enteric tablets, film-coated tablets,double-layered tablets or multiple-layered tablets.

[0058] In producing pills, usable as pharmaceutically acceptablecarriers are excipients such as glucose, lactose, starch, cacao butter,hydrogenated vegetable oil, kaolin and talc; binders such as gum arabicpowder, tragacanth powder, gelatin and ethanol; and disintegrators suchas laminaran and agar.

[0059] In producing suppositories, usable as pharmaceutically acceptablecarriers are polyethylene glycol, cacao butter, higher alcohols or theiresters, gelatin, semisynthetic glycerides and the like.

[0060] Capsules are usually manufactured in a conventional manner byblending the compound of the invention with one or more pharmaceuticallyacceptable carriers as exemplified above and encapsulating the mixtureinto hard gelatin capsule shells, soft gelatin capsule shells, etc.

[0061] When the compound of the invention is to be provided in aninjectable form such as a solution, an emulsion or a suspension, thepreparation is preferably sterilized and rendered isotonic to the blood.Diluents for use in such preparation include, for example, water,ethanol, macrogols, propylene glycol, ethoxylated isostearyl alcohol,polyoxyisostearyl alcohol, polyoxyethylene sorbitan fatty acid estersand the like. In this case, sodium chloride, glucose or glycerin may beadded to the pharmaceutical composition in an amount sufficient toprovide an isotonic solution. General solubilizers, buffers, soothingagents, etc., may also be added thereto.

[0062] In preparing ointments in the form of pastes, creams, gels, etc.,usable as diluents are white petrolatum, paraffin, glycerin, cellulosederivatives, polyethylene glycol, silicone, bentonite and the like.

[0063] Furthermore, if desired, coloring agents, preservatives,aromatics, flavors, sweeteners or other medicines may be incorporatedinto the pharmaceutical composition of the invention.

[0064] The proportion of the compound of the invention (activeingredient compound) in the pharmaceutical composition is not criticaland can be selected from a broad range. It is generally preferable thatthe compound account for about 0.5 to about 90 wt. %, preferably about 1to about 85 wt. % of the pharmaceutical composition.

[0065] There is no limitation to the methods for administering thepharmaceutical compositions of the invention. Thus, an appropriatemethod can be selected according to the dosage form, patient's age, sexand other conditions, severity of disease, etc. For example, tablets,pills, solutions, suspensions, emulsions, granules and capsules areorally administered. Injections are administered alone or in admixturewith glucose, amino acid or like conventional infusions by theintravenous route or by the intramuscular, intradermal, subcutaneous orintraperitoneal route, while suppositories are intrarectallyadministered.

[0066] The dosage of the pharmaceutical preparation of the invention issuitably selected according to the intended use, patient's age, sex andother conditions, severity of disease, etc., but may be such that thedosage of the compound of the invention as the active ingredient ispreferably about 0.5-20 mg, preferably about 1-10 mg, per kg body weighta day, for human adult. The pharmaceutical preparation may beadministered once a day or in 2-4 divided doses a day.

BEST MODE FOR CARRYING OUT THE INVENTION

[0067] Hereunder, to illustrate the present invention in more detail,examples of manufacturing methods of the starting compounds used inproducing the compounds of the present invention are described and thenmanufacturing methods of the compounds of the present invention aredescribed as Examples.

[0068] In each Example, unless otherwise stated, ¹H-NMR spectra weremeasured in dimethyl sulfoxide-d₆ (DMSO-d₆) solvent usingtetramethylsilane (TMS) as an internal standard.

REFERENCE EXAMPLE 1

[0069] (1) Manufacture of 1-benzyl-4-hydroxy-1,8-naphthyridine-2(1H)-one

[0070] In 400 ml of acetic anhydride was dissolved 36.7 g of methyl2-benzylaminonicotinate, followed by stirring at 160° C. for 48 hours.After completion of the reaction, acetic anhydride was removed underreduced pressure, the residue was dissolved in 400 ml of diethyl ether,washed twice with saturated sodium bicarbonate solution and once withwater, dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give 39.0 g of oily methyl2-(N-acetyl-N-benzyl)aminonicotinate.

[0071] Then, 22.5 g of the compound obtained above was dissolved in 300ml of xylene, 21.3 g of potassium-t-butoxide was added thereto at roomtemperature, and the mixture was stirred at 150° C. for 2 hours. Aftercooling, the mixture was extracted with 250 ml of water and aqueouscitric acid solution was added to the aqueous layer to adjust the pH ofthe aqueous layer to 3. The precipitated crystals were filtered andwashed with methanol, giving 20.5 g of crystalline1-benzyl-4-hydroxy-1,8-naphthyridine-2(1H)-one.

[0072] Melting point: 250-253° C.

[0073]¹H-NMR(δ: ppm): 5.55(2H, s), 5.97(1H, s), 7.15-7.35(6H, m),8.26(1H, d, J=7.7), 8.60(1H, d, J=4.7), 11.79(1H, brs)

[0074] (2)-(8) Manufacture of the Following Compounds

[0075] Following the procedure described in (1), and using appropriatestarting materials, compounds described in (2)-(8) below weresynthesized.

[0076] (2) 4-hydroxy-1,8-naphthyridine-2(1H)-one

[0077] Melting point: over 300° C.

[0078]¹H-NMR(δ: ppm): 5.76(1H, s), 7.21(1H, dd, J=4.7, 7.7), 8.14(1H, d,J=7.7), 8.51(1H, d, J=4.7), 11.58(2H, brs)

[0079] (3) 1-(4-methoxybenzyl)-4-hydroxy-1,8-naphthyridine-2(1H)-one

[0080] Melting point: 256-259° C.

[0081]¹H-NMR(δ: ppm): 3.69(3H, s), 5.48(2H, s), 5.96 (1H, s), 6.81(2H,d, J=8.7), 7.23(2H, d, J=8.7), 7.28(1H, dd, J=4.7, 7.7), 8.25(1H, d,J=7.7), 8.62(1H, d, J=4.7), 11.76(1H, brs)

[0082] (4)1-(3,4,5-trimethoxybenzyl)-4-hydroxy-1,8-naphthyridine-2(1H)-one

[0083] Melting point: 254-257° C.

[0084]¹H-NMR(δ: ppm): 3.60(3H, s), 3.67(6H, s), 5.47(2H, s), 5.96(1H,s), 6.60(2H, s), 7.30(1H, dd, J=4.7, 7.7), 8.26(1H, d, J=7.7), 8.64(1H,d, J=4.7), 11.80(1H, brs)

[0085] (5) 1-benzyl-4-hydroxy-7-methyl-1,8-naphthyridine-2(1H)-one

[0086] Melting point: 261-264° C.

[0087]¹H-NMR(δ:ppm): 2.49(3H, s), 5.49(2H, s), 5.87(1H, s), 7.10(1H, d,J=7.9), 7.12-7.29(5H, m), 8.09(1H, d, J=7.9), 11.78(1H, brs)

[0088] (6) 4-hydroxy-1-n-propyl-1,8-naphthyridine-2(1H)-one

[0089] Melting point: 257-259° C.

[0090]¹H-NMR(δ: ppm): 0.89(3H, t, J=7.4), 1.51-1.68(2H, m), 4.26(2H, t,J=7.4), 5.89(1H, s), 7.28(1H, dd, J=4.5, 7.6), 8.23(1H, d, J=7.6),8.64(1H, d, J=4.5), 11.70(1H, brs)

[0091] (7) 1-cyclohexyl-4-hydroxy-1,8-naphthyridine-2(1H)-one

[0092] Melting point: 265-268° C.

[0093]¹H-NMR(δ: ppm): 1.11-1.91(8H, m), 2.58-2.88(2H, m), 5.30-5.67(1H,m), 5.85(1H, s), 7.26(1H, dd, J=4.7, 7.7), 8.21(1H, d, J=7.7), 8.63(1H,d, J=4.7), 11.57(1H, brs)

[0094] (8) 4-hydroxy-1-phenyl-1,8-naphthyridine-2(1H)-one

[0095] Melting point: 288-290° C.

[0096]¹H-NMR(δ:ppm): 5.94(1H, s), 7.17-7.30(3H, m), 7.35-7.52(3H, m),8.26(1H, d, J=7.9), 8.39(1H, d, J=4.7), 11.51(1H, brs)

[0097] (9) Manufacture of1-benzyl-3-phenyliodonium-1,8-naphthyridine-2(1H)-one-4-olate

[0098] Sodium carbonate (3.1 g) (29 mmol) was dissolved in 200 ml ofwater in which 7.0 g (28 mmol) of compound (1) was then dissolved.Further, 9.0 g (28 mmol) of iodobenzene diacetate was added thereto atroom temperature, followed by stirring for 5 hours. After completion ofthe reaction, the crystals precipitated were collected by filtration,washed sequentially with water, methanol and ether, and dried underreduced pressure at room temperature for 20 hours to give 10.1 g of thetitle compound.

[0099] Melting point: 147-149° C. (decomposition)

[0100]¹H-NMR(δ: ppm): 5.56(2H, s), 7.11-7.26(6H, m), 7.33-7.54(3H, m),7.84(2H,d, J=7.4), 8.32(1H, d, J=7.4), 8.50(1H, d, J=4.5)

[0101] (10)-(16) Manufacture of the Following Compounds

[0102] Following the procedure described in (9), and using appropriatestarting materials, compounds (10)-(16) described below weresynthesized.

[0103] (10) 3-phenyliodonium-1,8-naphthyridine-2(1H)-one-4-olate

[0104] Melting point: over 300° C.

[0105]¹H-NMR(δ: ppm): 7.10(1H, dd, J=4.7, 7,7), 7.35-7.53(3H, m),7.81(2H, d, J=7.4), 8.20(1H, d, J=7.7), 8.42(1H, d, J=4.7), 11.01(1H, s)

[0106] (11)1-(4-methoxybenzyl)-3-phenyliodonium-1,8-naphthyridine-2(1H)-one-4-olate

[0107] Melting point: 128-130° C.

[0108]¹H-NMR(δ: ppm): 3.68(3H, s), 5.48(2H, s), 6.80(2H, d, J=8.9),7.15(1H, dd, J=4.9, 7.9), 7.22(1H, d, J=8.9), 7.36-7.55(3H, m), 7.84(1H,d, J=7.4), 8.31(1H, d, J=7.9), 8.51(1H, d, J=4.9)

[0109] (12)3-phenyliodonium-1-(3,4,5-trimethoxybenzyl)-1,8-naphthyridine-2(1H)-one-4-olate

[0110] Melting point: 132-134° C.

[0111]¹H-NMR(δ: ppm): 3.58(3H, s), 3.60(3H, s), 5.48(2H, s), 6.56(2H,s), 7.16(1H, dd, J=4.7, 7.7), 7.35-7.55(3H, m), 7.86(2H, d, J=7.7),8.33(1H, d, J=7.7), 8.52(1H, d, J=4.7)

[0112] (13)1-benzyl-7-methyl-3-phenyliodonium-1,8-naphthyridine-2(1H)-one-4-olate

[0113] Melting point: 139-140° C.

[0114]¹H-NMR(δ: ppm): 2.47(3H, s), 5.53(2H, s), 7.01(1H, d, J=7.9),7.10-7.53(8H, m), 7.83(2H, d, J=8.4), 8.20(1H, d, J=7.9)

[0115] (14)3-phenyliodonium-1-n-propyl-1,8-naphthyridine-2(1H)-one-4-olate

[0116] Melting point: 133-135° C.

[0117]¹H-NMR(δ: ppm) [CDCl₃]: 0.91(3H, t, J=7.5), 1.45-1.61(2H, m),4.20(2H, t, J=7.6), 7.04(1H, dd, J=4.6, 7.6), 7.32-7.50(3H, m), 7.94(2H,d, J=8.5), 8.38(1H, d, J=7.6), 8.47(1H, d, J=4.6)

[0118] (15)1-cyclohexyl-3-phenyliodonium-1,8-naphthyridine-2(1H)-one-4-olate

[0119] Melting point: 136-138° C.

[0120]¹H-NMR(δ: ppm): 1.13-1.87(8H, m), 2.50-2.75(2H, m), 5.30-5.50(1H,m), 7.14(1H, dd, J=4.6, 7.7), 7.35-7.53(3H, m), 7.83(2H, d, J=8.2),8.30(1H, d, J=7.7), 8.53(1H, d, J=4.6)

[0121] (16)1-phenyl-3-phenyliodonium-1,8-naphthyridine-2(1H)-one-4-olate

[0122] Melting point: 141-143° C.

[0123]¹H-NMR(δ: ppm)[CDCl₃]: 7.07(1H, dd, J=4.6, 7.6), 7.22(1H, d,J=7.3), 7.31-7.56(6H, m), 8.01(2H, d, J=7.6), 8.39(1H, d, J=4.6),8.49(1H, d, J=7.6)

[0124] (17)-(20) Manufacture of the Following Compounds

[0125] Following the procedure described in (1), and using appropriatestarting materials, compounds described in (17) and (18) below weresynthesized. Compounds described in (19) and (20) below were synthesizedfollowing the procedure described in (9), and using appropriate startingmaterials.

[0126] (17) 1-ethyl-4-hydroxy-1,8-naphthyridine-2(1H)-one

[0127] (18) 4-hydroxy-1-methyl-1,8-naphthyridine-2(1H)-one

[0128] (19) 1-ethyl-3-phenyliodonium-1,8-naphthyridine-2(1H)-one-4-olate

[0129] (20)1-methyl-3-phenyliodonium-1,8-naphthyridine-2(1H)-one-4-olate

EXAMPLE 1 Manufacture of1-benzyl-3-[methyl-3-(3,4,5-trimethoxyphenoxy)propylsulfonium]-1,8-naphthyridine-2(1H)-one-4-olate

[0130] The compound obtained in (9) (2.3 g, 5.1 mmol), 1.7 g (6.2 mmol)of methyl-3-(3,4,5-trimethoxyphenoxypropyl)sulfide and 30 mg ofp-toluenesulfonic acid were dissolved in 20 ml of trifluoroethanol andstirred at room temperature for 30 minutes. After completion of thereaction, the trifluoroethanol was evaporated off and the residue waspurified by silica gel column chromatography (developing solvent;methanol:chloroform=1:25). The crystals obtained were washed withmethanol to provide 2.4 g of the title compound.

EXAMPLES 2-38

[0131] Compounds of the invention having the structures shown in Tables1-5 below were prepared following the procedure of Example 1. Subsequenttables show the melting points and ¹H-NMR analyses of the compounds.TABLE 1 Example 1 Example 2 Structral Formula: Structral Formula:

Example 3 Example 4 Structral Formula: Structral Formula:

Example 5 Example 6 Struactral Formula: Structral Formula:

Example 7 Example 8 Structral Formula: Structral Formula:

Example 9 Example 10 Structral Formula: Structral Formula:

[0132] TABLE 2 Example 11 Example 12 Structral Formula: StructralFormula:

Example 13 Example 14 Structral Formula: Structral Formula:

Example 15 Example 16 Structral Formula: Structral Formula:

Example 17 Example 18 Structral Formula: Structral Formula:

Example 19 Example 20 Structral Formula: Structral Formula:

[0133] TABLE 3 Example 21 Example 22 Structral Formula: StructralFormula:

Example 23 Example 24 Structral Formula: Structral Formula:

Example 25 Example 26 Structral Formula: Structral Formula:

Example 27 Example 28 Structral Formula: Structral Formula:

[0134] TABLE 4 Example 29 Example 30 Structral Formula: StructralFormula:

Example 31 Example 32 Structral Formula: Structral Formula:

Example 33 Example 34 Structral Formula: Structral Formula:

Example 35 Example 36 Structral Formula: Structral Formula:

[0135] TABLE 5 Example 37 Example 38 Structral Formula: StructralFormula:

[0136] TABLE 6 Example Melting point Example Melting point No. (° C.)No. (° C.) 1 147-149 2 130-132 3 145-147 4 161-163 5 165-167 6 157-159 7124-126 8 84-87 9 132-134 10 121-123 11 158-160 12 120-122 13 100-102 14165-167 15 135-137 16 114-116 17 203-205 18 183-186 19 151-153 20123-124 21 101-103 22 126-128 23 84-86 24 123-124 25 136-138 26 100-10227 89-91 28 156-157 29 220-222 30 161-163 31 203-205 32 120-122 33182-184 34 96-98 35 110-113 36 186-188 37 157-159 38 164-166

[0137] TABLE 7 Example No. ¹H-NMR (δ: ppm) 1 1.95-2.10(2H, m), 3.18(3H,s), 3.43-3.55(1H, m), 3.56(3H, s), 3.70(6H, s), 4.02(2H, t, J=6.4),4.07-4.20(1H, m), 5.45(2H, s), 6.19(2H, s), 7.16(1H, dd, J=4.5, 7.4),7.19- 7.25(5H, m), 8.28(1H, d, J=7.4), 8.48(1H, d, J=4.5) 2 3.13(3H, s),3.53-3.62(1H, m), 3.66-3.83(2H, m), 4.13- 4.24(1H, m), 4.45(2H, s),5.47(2H, s), 7.10-7.30(11H, m), 8.30(1H, d, J=7.6), 8.50(1H, d, J=4.6) 33.12(3H, s), 3.50-3.59(1H, m), 3.65-3.82(2H, m), 4.13- 4.26(1H, m),4.43(2H, s), 5.46(2H, m), 7.14-7.30(10H, m), 8.29(1H, d, J=7.4),8.50(1H, d, J=4.9) 4 2.27(6H, s), 3.60(3H, s), 3.52-3.65(1H, m),3.66-3.86(2H, m), 4.08-4.20(1H, m), 4.45(2H, s), 5.47(2H, s), 6.92-7.09(3H, m), 5.96(1H, s), 7.17(1H, dd, J=4.8, 7.6), 8.27(1H, d, J=7.6),8.49(1H, d, J=4.8) 5 2.16(3H, s), 2.22(3H, s), 3.08(3H, s),3.46-3.61(1H, m), 3.64-3.83(2H, m), 4.08-4.19(1H, m), 4.41(2H, s),5.46(2H, s), 6.77(2H, s), 7.17(1H, dd, J=4.5, 7.4), 7.18-7.29(5H, m),8.27(1H, d, J=7.4), 8.49(1H, d, J=4.5) 6 3.16(3H, s), 3.59-3.80(2H, m),3.87-3.97(1H, m), 4.18- 4.29(1H, m), 4.58(2H, s), 5.45(2H, s),7.08-7.24(6H, m), 7.95-8.05(3H, m), 8.27(1H, d, J=7.9), 8.49(1H, d,J=4.6) 7 3.12(3H, s), 3.45-3.58(1H, m), 3.65-3.79(2H, m), 4.10- 4.19(1H,m), 4.32(2H, s), 5.47(2H, s), 5.94(2H, d, J=7.9), 6.74(2H, s), 6.87(1H,s), 7.10-7.24(6H, m), 8.29(1H, d, J=7.4), 8.49(1H, d, J=4.5)

[0138] TABLE 8 Ex- ample No. ¹H-NMR(δ: ppm) 8 3.12(3H, s), 3.45-3.60(1H,m), 3.65-3.77(2H, m), 3.78(3H, s), 4.11-4.20(1H, m), 4.32(2H, s),5.47(2H, s), 5.91(2H, d, J=6.4), 6.54(1H, s), 6.60(1H, s), 7.12-7.23(6H,m), 8.26(1H, d, J=7.9), 8.48(1H, d, J=4.5) 9 3.13(3H, s), 3.50-3.61(1H,m), 3.62(3H, s), 3.72(3H, s), 3.73-3.84(2H, m), 4.07-4.18(1H, m),4.30(2H, s), 5.48(2H, s), 6.42(1H, s), 6.45(1H, s), 7.17(1H, dd, J=4.9,7.9), 7.18-7.26(5H, m), 8.29(1H, d, J=7.9), 8.49(1H, d, J=4.9) 103.12(3H, s), 3.47-3.61(1H, m), 3.71(3H, s), 3.75-3.82(2H, m),4.08-4.17(1H, m), 4.31(2H, s), 5.48(2H, s), 6.58(2H, s), 7.17(1H, dd,J=4.5, 7.9), 7.18-7.27(5H, m), 8.25(1H, d, J=7.9), 8.49(1H, d, J=4.5) 113.16(3H, s), 3.84-3.96(1H, m), 4.07-4.18(1H, m), 4.31- 4.43(2H, m),6.90-6.99(3H, m), 7.09(1H, dd, J=4.7, 7.9), 7.23- 7.33(2H, m), 8.14(1H,d, J=7.9), 8.41(1H, d, J=4.7), 10.84(1H, brs) 12 3.20(3H, s),3.85-3.96(1H, m), 4.08-4.19(1H, m), 4.31- 4.44(2H, m), 5.45(2H, s),6.87-6.97(3H, m), 7.18-7.29(8H, m), 8.27(1H, d, J=7.4), 8.48(1H, d,J=4.5) 13 3.10(3H, s), 3.45(3H, s), 3.55(3H, s), 3.80-3.90(1H, m),4.10-4.21(1H, m), 4.30-4.41(2H, m), 5.35(2H, s), 6.09(2H, s),7.11-7.24(6H, m), 8.27(1H, d, J=7.4), 8.48(1H, d, J=4.9) 14 3.18(3H, s),3.56(3H, s), 3.70(9H, s), 3.80-3.94(1H, m), 4.09-4.18(1H, m),4.31-4.45(1H, m), 5.45(2H, s), 6.19(2H, s), 6.83(2H, d, J=8.9),7.12-7.20(3H, m), 8.27(1H, d, J=7.6), 8.48(1H, d, J=4.6)

[0139] TABLE 9 Ex- ample No. ¹H-NMR(δ: ppm) 15 3.20(3H, s), 3.55(3H, s),3.57(6H, s), 3.61(6H, s), 3.64 (6H, s), 3.79-3.91(1H, m), 4.11-4.20(1H,m), 4.32-4.46(2H, m), 5.40(2H, s), 6.18(2H, s), 6.59(2H, s), 7.17(1H,dd, J=4.5, 7.4), 8.27(1H, d, J=7.4), 8.53(1H, d, J=4.5) 16 2.45(3H, s),3.18(3H, s), 3.55(3H, s), 3.65(6H, s), 3.80- 3.94(1H, m), 4.08-4.18(1H,m), 4.30-4.43(2H, m), 5.43(2H, s), 6.18(2H, s), 7.02(1H, d, J=7.9),7.13-7.29(5H, m), 8.13(1H, d, J=7.9) 17 3.16(3H, s), 3.76(3H, s),3.79(3H, s), 3.83-3.95(1H, m), 4.15-4.23(1H, m), 4.30-4.49(2H, m),7.01(2H, d, J=8.9), 7.08(1H, dd, J=4.5, 7.4), 7.42(2H, d, J=8.9),7.68(1H, s), 8.11(1H, d, J=7.4), 8.41(1H, d, J=4.5), 10.84(1H, brs) 183.00(2H, d, J=7.9), 3.15(3H, s), 3.59(6H, s), 3.77-3.94(2H, m),4.02-4.15(1H, m), 4.25-4.37(2H, m), 6.83(2H, d, J=8.9), 7.05-7.15(3H,m), 7.42(2H, d, J=8.9), 8.13(1H, d, J=7.9), 8.41(1H, d, J=4.9),10.83(1H, brs) 19 3.21(3H, s), 3.77(3H, s), 3.79(3H, s), 3.82-3.95(1H,m), 4.15-4.27(1H, m), 4.34-4.51(2H, m), 5.43(2H, s), 6.97(2H, d, J=8.9),7.10-7.19(6H, m), 7.40(2H, d, J=8.9), 7.67(1H, s), 8.25(1H, d, J=7.4),8.48(1H, d, J=4.8) 20 3.00(2H, d, J=8.1), 3.19(3H, s), 3.59(6H, s),3.75-3.82(1H, m), 3.83-3.94(1H, m), 4.05-4.17(1H, m), 4.27-4.40(2H, m),5.45(2H, s), 6.80(2H, d, J=8.1), 7.07(2H, d, J=8.1), 7.11- 7.24(6H, m),8.26(1H, d, J=7.4), 8.47(1H, d, J=4.8)

[0140] TABLE 10 Ex- ample No. ¹H-NMR(δ: ppm) 21 1.93-2.10(2H, m),3.17(3H, s), 4.04(2H, t, J=6.3), 4.06- 4.17(1H, m), 5.46(2H, s),6.83-6.92(3H, m), 7.16(1H, dd, J=4.6, 7.6), 7.17-7.28(7H, m), 8.27(1H,d, J=7.6), 8.49(1H, d, J=4.6) 22 1.92-2.08(2H, m), 3.14(3H, s),3.39-3.55(1H, m), 3.56(3H, s), 3.73(6H, s), 3.96-4.15(3H, m), 6.21(2H,s), 7.09(1H, dd, J=4.5, 7.9), 8.15(1H, d, J=7.9), 8.41(1H, d, J=4.5),10.86(1H, brs) 23 0.88(3H, t, J=7.4), 1.50-1.69(2H, m), 1.91-2.08(2H,m), 3.16(3H, s), 3.40-3.54(1H, m), 3.56(3H, s), 3.71(6H, s), 4.01(2H, t,J=5.9), 4.08-4.22(3H, s), 6.18(2H, s), 7.15(1H, dd, J=4.5, 7.9),8.26(1H, d, J=7.9), 8.54(1H, d, J=4.5) 24 1.94-2.07(2H, m), 2.45(3H, s),3.16(3H, s), 3.40-3.55(1H, m), 3.56(3H, s), 3.70(6H, s), 3.97-4.05(2H,m), 4.06- 4.19(1H, m), 5.43(2H, s), 6.18(2H, s), 7.02(1H, d, J=7.9),7.13-7.31(6H, m), 8.14(1H, d, J=7.9) 25 1.93-2.08(2H, m), 3.17(3H, s),3.43-3.54(1H, m), 3.56(3H, s), 3.66(3H, s), 3.70(6H, s), 3.95-4.03(2H,m), 4.04- 4.20(1H, m), 5.37(2H, s), 6.19(2H, s), 6.78(2H, d, J=8.6),7.16(1H, dd, J=4.5, 7.6), 7.21(2H, d, J=8.6), 8.27(1H, d, J=7.6),8.50(1H, d, J=4.6) 26 1.91-2.09(2H, m), 3.18(3H, s), 3.40-3.55(1H, m),3.56(3H, s), 3.65(3H, s), 3.70(6H, s), 3.97-4.08(2H, m), 4.09- 4.22(1H,m), 5.40(2H, s), 6.19(2H, s), 6.58(2H, s), 7.17(1H, dd, J=4.5, 7.9),8.28(1H, d, J=7.9), 8.52(1H, d, J=4.5)

[0141] TABLE 11 Ex- ample No. ¹H-NMR(δ: ppm) 27 1.10-1.83(8H, m),2.52-2.75(2H, m), 3.61(6H, s), 3.75- 3.90(6H, m), 4.10-4.21(2H, m),4.35(4H, s), 5.23-5.47(1H, m), 6.62(4H, s), 7.15(1H, dd, J=4.7, 7.7),8.25(1H, d, J=7.7), 8.53(1H, d, J=4.7) 28 3.60(6H, s), 3.67(12H, m),3.68-3.89(6H, m), 4.10-4.20(2H, m), 4.37(4H, s), 6.61(4H, s),7.10-7.18(3H, m), 7.37- 7.49(3H, m), 8.25-8.37(2H, m) 29 3.16(3H, s),3.55(3H, s), 3.70(6H, s), 3.71-3.88(1H, m), 4.06-4.18(1H, m),4.28-4.45(2H, m), 6.22(2H, s), 7.10(1H, dd, J=4.7, 7.7), 8.14(1H, d,J=7.7), 8.40(1H, d, J=4.7), 10.85(1H, brs) 30 1.75-1.93(2H, m), 3.12(3H,s), 3.40-3.55(3H, m), 3.63(3H, s), 3.76(6H, s), 3.90-4.05(1H, m),4.36(2H, s), 6.61(2H, s), 7.09(1H, dd, J=4.9, 7.9), 8.13(1H, d, J=7.9),8.41(1H, d, J=4.9), 10.84(1H, brs) 31 3.61(3H, s), 3.65-3.90(8H, m),4.25-4.35(1H, m), 4.41(2H, s), 4.65-4.75(1H, m), 6.63(2H, s), 7.12(1H,dd, J=4.7, 7.7), 7.51-7.61(3H, m), 7.81-7.90(2H, m), 8.17(1H, d, J=7.7),8.45(1H, d, J=4.7), 11.00(1H, brs) 32 1.18(3H, t, J=7.4), 1.91-2.08(2H,m), 3.30-3.50(2H, m), 3.56(3H, s), 3.72(6H, s), 3.95-4.15(4H, m),6.20(2H, s), 7.09(1H, dd, J=4.9, 7.9), 8.13(1H, d, J=7.9), 8.41(1H, d,J=4.9), 10.85(1H, brs)

[0142] TABLE 12 Ex- ample No. ¹H-NMR(δ: ppm) 33 3.54(3H, s), 3.68(3H,s), 3.77-3.86(1H, m), 4.05-4.17(1H, m), 4.33-4.40(1H, m), 4.48-4.57(1H,m), 4.76(1H, d, J=12.0), 5.39(1H, d, J=12.0), 6.20(2H, s), 7.08(1H, dd,J=4.4, 7.2), 8.11(1H, d, J=7.2), 8.40(1H, d, J=4.4) 34 1.20(3H, t,J=7.4), 1.95-2.11(2H, m), 3.35-3.52(2H, m), 3.56(3H, s), 3.69(6H, s),3.95-4.05(3H, m), 4.05-4.20(1H, m), 5.46(2H, s), 6.18(2H, s),7.11-7.26(6H, m), 8.27(1H, d, J=7.9), 8.48(1H, d, J=5.0) 351.97-2.17(2H, m), 3.56(3H, s), 3.57-3.68(1H, m), 3.69(6H, s), 4.03(2H,t, J=6.4), 4.21-4.35(1H, m), 4.75(1H, d, J=11.4), 5.33-5.43(3H, m),6.17(2H, s), 7.03-7.35(1H, m), 8.23(1H, d, J=7.4), 8.44(1H, d, J=5.0) 363.17(3H, s), 3.50(3H, s), 3.55(3H, s), 3.69(6H, s), 3.80- 3.88(1H, s),4.10-4.18(1H, m), 4.31-4.42(2H, m), 6.20(2H, s), 7.17(1H, dd, J=4.8,7.6), 8.25(1H, d, J=7.6), 8.55(1H, d, J=4.8) 37 1.12(3H, t, J=6.8),3.18(3H, s), 3.54(3H, s), 3.68(6H, s), 3.80-3.89(1H, m), 4.08-4.18(1H,m), 4.27(2H, q, J=6.8), 4.30-4.41(2H, m), 6.19(2H, s), 7.16(1H, dd,J=4.8, 7.6), 8.25(1H, d, J=7.6), 8.55(1H, d, J=4.8) 38 1.91-2.13(2H, m),3.47-3.50(1H, m), 3.54(3H, s), 3.72(6H, s), 4.02(2H, t, J=5.6), 4.74(1H,d, J=11.6), 5.39(1H, d, J=11.6), 6.19(2H, s), 7.07(1H, dd, J=4.4, 7.6),7.31(5H, s), 8.11(1H, d, J=7.6), 8.39(1H, d, J=4.4), 10.80(1H, brs)

Pharmacological Test 1 Therapeutic Effect on Diabetic Neuropathy

[0143] A model group was obtained by intravenously administering 50mg/kg streptozotocin (STZ) dissolved in 0.01 M citrate buffer solutionto 8-week-old male S.D. rats. After administration, five rats werehoused per cage and kept therein.

[0144] Three weeks after administration of STZ, the pain threshold ofeach rat's left hind paw to pressure stimulation was measured byRandall-Selitto Test [Randall, L. O. and Selitto, J. J. Arch. Int.Pharmacodyn., 111, 409-419 (1957)]. The value thus obtained was termed“pre-value”.

[0145] Rats exhibiting a pre-value of 30 mmHg or less were chosen anddivided into three groups so that each group had 8-10 rats (n=8-10).

[0146] A 5% gum arabic solution containing the test compound was orallyadministered as specimen to experimental animals in one of the abovethree groups (test group) in such a manner that each dosage of the testcompound was 30 mg/kg and the amount of administered solution was 10ml/kg, once a day for 21 continuous days. Another group was defined asthe control group, and only a 5% gum arabic solution was administered asspecimen to experimental animals in the control group in such a mannerthat each dosage was 10 ml/kg, once a day for 21 continuous days.Finally, in the third group no specimen was administered to theexperimental animals (non-treated group).

[0147] On the 14^(th) and 21^(st) days, the pain threshold of the lefthind paw of the experiment animals was measured three hours afteradministration. The recovery rate (%) of the pain threshold wascalculated by means of the following formula:

Recovery rate (%)=[(T−C)/(N−C)]×100

[0148] (wherein T is the test group average value, C is the controlgroup average value and N is the non-treated group average value.)

[0149] Table 13 below shows the results. TABLE 13 Recovery rate (%) Testcompound 14^(th) day 21^(st) day Example 1 46.2 56.7

[0150] As is clear from the results shown in Table 13, the compound ofthe present invention exhibits excellent effects in treating diabeticneuropathy.

Pharmacological Test 2 Adenosine Enhancing Effect

[0151] The compounds obtained in Examples 1 and 34 were used as testcompounds in the form of a dimethyl sulfoxide solution.

[0152] As experimental animals, Hartley male guinea pigs (purchased fromCHARLES RIVER JAPAN, INC.) (that were in good general condition at least6 days after the purchase) were used. The animals were housed in a cageunder controlled conditions of temperature of 20 to 26° C. (actuallymeasured value: 22.1 to 22.9° C.), humidity of 40-70% (actually measuredvalue: 50.3-51.5%) and lighting of 12 hours/day (7:00-19:00). Theanimals had free access to food (solid diet, product name of Labo GStandard, product of Nosan Corporation) and tap water.

[0153] The following experiments were conducted using the excised ilea(n=2) of experimental animals (body weight at the time of testing:316-388 g). The experimental animals were bled and slaughtered. Theileum thereof was extracted and suspended under a tension of 0.5 g in abath (organ bath) filled with a nutrient solution (Krebs-Henseleitsolution; amount=10 mL, solution temperature=32° C.) gassed with a mixedgas of 95% oxygen+5% carbon dioxide. Contraction by transmuralelectrical stimulation was induced using an electronic stimulator(product of NIHON KOHDEN CORPORATION, SEN-3301) and 4 channel bus driveamplifier (product of NIHON KOHDEN CORPORATION, SEG-3104) by applyingrectangular wave electronic stimulation (frequency: 0.1 Hz, duration: 5msec, voltage: sub-maximum voltage (V)) via ring-shaped platinumelectrodes. The contraction reaction of samples was recorded on anink-writing recorder (GRAPHTEC, SR-6211, SR-6221) through an isotonictransducer (product of NIHON KOHDEN CORPORATION, TD-112S).

[0154] While exchanging the nutrient solution about every 20 minutes,the samples were left in the nutrient solution for 30-60 minutes, andthen electric stimulation was applied thereto. After the contractionreaction stabilized, 10⁻⁶ M to 10⁻⁵ M of adenosine (product of Wako PureChemical Industries, Ltd) was cumulatively added thereto, and reductionof contraction reaction was monitored as below.

[0155] That is, the nutrient solution was exchanged, electronicstimulation was applied to the samples 15 minutes after exchange of thenutrient solution, and, when contraction stabilized, adenosine wascumulatively added from 10⁻⁶ M to 10⁻⁵ M. The adenosine dose-responsecurve was then obtained, and the ED₅₀ value was calculated.

[0156] The nutrient solution was then exchanged and electronicstimulation was again applied to the samples 15 minutes later. When thecontraction stabilized, test compounds having a final concentration of10⁻⁷ M, 10⁻⁶ M and 10 M⁻⁵ were added thereto and reacted for 5 minutes.Thereafter, adenosine was cumulatively added from 10⁻⁶ M to 10⁻⁵ M, andthe adenosine dose-response curve was then obtained and the ED₅₀ value[ED₅₀(+)] of adenosine in the presence of the test compound wascalculated.

[0157] The adenosine enhancement effect was then determined as the ratioof the ED₅₀ value in the absence of the test compound [ED₅₀(−)], i.e.,(ED₅₀(−)/ED₅₀(+)).

[0158] The obtained results were shown in Table 14 below. TABLE 14Adenosine enhancing Test Concentration effect compound (M)(ED₅₀(−)/ED₅₀(+)) Example 1  10⁻⁶ 11.11 Example 34 10⁻⁵ 14.00

[0159] As seen from the results shown in Table 14, it is clear that thecompounds of the present invention exhibit excellent adenosine enhancingeffects.

Pharmacological Test 3 Test for Evaluating Analgesic Effect

[0160] Using two groups (test group and control group) each consistingof 6-week-old male S.D. rats (7 rats in each group), the pain thresholdof each rat's left hind paw was measured using an Analgesy-meter(product of Unicom) in accordance with the Randall-Sellitto method[Randall, L. O. and Sellitto, J. J., Arch. Int. Pharmacodyn., 111,409-419 (1957)]. The value thus obtained was termed “pre-value”.

[0161] One hour after the measurement of the pre-value, a 5% gum arabicsuspension containing compound of the invention was orally administeredto the rats of the test group in an amount of 10 ml/kg, whereas a 5% gumarabic suspension (not containing compound of the invention) was orallyadministered to the rats of the control group in an amount of 10 ml/kg.

[0162] One hour after the oral administration, a physiological salinesolution containing Substance P (25 ng/0.1 ml) was subcutaneouslyinjected into the left hind paw of each rat.

[0163] The pain threshold of each rat's left hind paw was measured inthe same manner as above at predetermined time intervals after theSubstance P injection. The measured value is termed the “post-value”.

[0164] The recovery rate (%) of the pain threshold was calculated fromthe post-values and pre-values of the test group and control group, bymeans of the following formula: $\begin{matrix}{{Recovery}\quad {rate}\quad {of}} \\{{pain}\quad {threshold}\quad (\%)}\end{matrix} = {\frac{\begin{matrix}\left\lbrack {\left( {{test}\quad {group}\quad {average}\quad {post}\quad {value}} \right) -} \right. \\\left. \left( {{control}\quad {group}\quad {average}\quad {post}\quad \text{-}{value}} \right) \right\rbrack\end{matrix}}{\begin{matrix}\left\lbrack {\left( {{control}\quad {group}\quad {average}\quad {pre}\text{-}{value}} \right) -} \right. \\\left. \left( {{control}\quad {group}\quad {average}\quad {post}\quad \text{-}{value}} \right) \right\rbrack\end{matrix}} \times 100}$

[0165] Table 15 shows the results (highest recovery rate). TABLE 15Measurement point Test Recovery rate (minutes after compound (%)injection) Example 1  46 60 Example 15 39 60 Example 36 111  60

[0166] From the results shown in Table 15, it is clear that thecompounds obtained in Examples 1, 15 and 36 of the invention exhibit anexcellent analgesic effect.

[0167] Furthermore, the compounds shown in Tables 16 and 17 below canalso be produced in the same manner as in the above-described Examples.These compounds belong to group (8) of the invention described above.When these compounds are subjected to the tests as described in theabove Pharmaceutical Tests, they are considered to achieve substantiallythe same results as shown in Tables 13-15. TABLE 16 Compound 101Compound 102

Compound 103 Compound 104

Compound 105 Compound 106

Compound 107 Compound 108

Compound 109 Compound 110

Compound 111 Compound 112

Compound 113 Compound 114

Compound 115

[0168] TABLE 17 Compound 116 Compound 117

Compound 118 Compound 119

Compound 120 Compound 121

Compound 122

FORMULATION EXAMPLE 1

[0169] Tablets (2000 tables), each containing as an active ingredient300 mg of the compound of the invention obtained in Example 1, weremanufactured according to the following formulation: Compound of theinvention obtained in Example 1 600 g Lactose (Japanese pharmacopoeia) 67 g Corn starch (Japanese pharmacopoeia)  33 g Carboxymethyl cellulosecalcium  25 g (Japanese pharmacopoeia) Methyl cellulose (Japanesepharmacopoeia)  12 g Magnesium stearate (Japanese pharmacopoeia)  3 g

[0170] More specifically, the compound of the invention obtained inExample 1, lactose, corn starch and carboxymethyl cellulose calcium werewell blended and granulated using an aqueous methyl cellulose solution.The granulated mixture was passed through a 24-mesh sieve, and thegranules under the sieve were mixed with magnesium stearate andcompression-molded to give the desired tablets.

FORMULATION EXAMPLE 2

[0171] Hard gelatin capsules (2000 capsules), each containing as anactive ingredient 200 mg of the compound of the invention obtained inExample 25, were manufactured according to the following formulation:Compound of the invention obtained in Example 25 400 g Crystallinecellulose (Japanese pharmacopoeia)  60 g Corn starch (Japanesepharmacopoeia)  34 g Talc (Japanese pharmacopoeia)  4 g Magnesiumstearate (Japanese pharmacopoeia)  2 g

[0172] More specifically, the above ingredients were finely pulverizedand blended to give a homogeneous mixture. This mixture was placed inappropriately sized gelatin capsule shells for oral administration toprovide the desired capsules.

1. A naphthyridine derivative represented by the following generalformula (1):

wherein R¹ represents a hydrogen atom or a lower alkyl group; R²represents a hydrogen atom, a lower alkyl group, a cycloalkyl group,phenyl group, or a phenyl-lower alkyl group optionally having 1 to 3lower alkoxy groups on the phenyl ring; R³ and R⁴ each independentlyrepresent the group —Y—O—Z—R⁵ (wherein Y is a lower alkylene group, Z isa single bond or a lower alkylene group, and R⁵ is phenyl groupoptionally having 1 to 3 substituents selected from the group consistingof halogen atoms, lower alkoxy groups, lower alkyl groups,halogen-substituted lower alkyl groups, methylenedioxy group, hydroxylgroup, 2,2-di(lower alkoxy-carbonyl)ethyl groups and 2,2-di(loweralkoxy-carbonyl)vinyl groups, or one of R³ and R⁴ is the group —Y—O—Z—R⁵(wherein Y, Z and R⁵ are as above) and the other is a lower alkyl group,phenyl group, or a phenyl-lower alkyl group; with the proviso that thecase where R² is a phenyl-lower alkyl group optionally having 1 to 3lower alkoxy groups on the phenyl ring and at least one of R³ and R⁴ isa benzyloxy-lower alkyl group having 1 to 3 lower alkoxy groups on thebenzene ring is excluded.
 2. A naphthyridine derivative according toclaim 1, wherein one of R³ and R⁴ is a lower alkyl group.
 3. Anaphthyridine derivative according to claim 1, wherein R¹ is a hydrogenatom and either R³ or R⁴ is a lower alkyl group.
 4. A naphthyridinederivative according to claim 1, wherein R¹ is a hydrogen atom, R² is aphenyl-lower alkyl group optionally having 1 to 3 lower alkoxy groups onthe phenyl ring and either R³ or R⁴ is a lower alkyl group.
 5. Anaphthyridine derivative according claim 1, wherein R¹ is a hydrogenatom, R² is a phenyl-lower alkyl group optionally having 1 to 3 loweralkoxy groups on the phenyl ring, one of R³ and R⁴ is a lower alkylgroup and Z is a single bond.
 6. A naphthyridine derivative according toclaim 1, wherein R¹ is a hydrogen atom, R² is a phenyl-lower alkyl groupoptionally having 1 to 3 lower alkoxy groups on the phenyl ring, one ofR³ and R⁴ is a lower alkyl group, R⁵ is phenyl group having 1 to 3 loweralkoxy groups as substituents and Z is a single bond.
 7. A naphthyridinederivative according to claim 1, wherein R¹ is a hydrogen atom, R² isbenzyl optionally substituted with 1 to 3 lower alkoxy groups on thephenyl ring, one of R³ and R⁴ is a lower alkyl group, R⁵ is phenyl grouphaving 1 to 3 lower alkoxy groups as substituents and Z is a singlebond.
 8. A naphthyridine derivative according to claim 1, wherein one ofR³ and R⁴ is a lower alkyl group and Z is a single bond.
 9. Anaphthyridine derivative according to claim 1, wherein one of R³ and R⁴is a lower alkyl group, R⁵ is phenyl group having 3 lower alkoxy groupsas substituents and Z is a single bond.
 10. A naphthyridine derivativeaccording to claim 1, wherein one of R³ and R⁴ is a lower alkyl group,R⁵ is a 3,4,5-tri-lower alkoxy-phenyl group and Z is a single bond. 11.A naphthyridine derivative according to claim 1, which is selected fromthe group consisting of1-(3,4,5-trimethoxybenzyl)-3-[methyl-2-(3,4,5-trimethoxyphenoxy)ethylsulfonium]-1,8-naphthyridine-2(1H)-one-4-olate,1-benzyl-3-[ethyl-3-(3,4,5-trimethoxyphenoxy)propylsulfonium]-1,8-naphthyridine-2(1H)-one-4-olate,1-methyl-3-[methyl-2-(3,4,5-trimethoxyphenoxy)ethylsulfonium]-1,8-naphthyridine-2(1H)-one-4-olate,1-benzyl-3-[methyl-3-(3,4,5-trimethoxyphenoxy)propylsulfonium]-1,8-naphthyridine-2(1H)-one-4-olate,and1-(4-methoxybenzyl)-3-[methyl-3-(3,4,5-trimethoxyphenoxy)propylsulfonium]-1,8-naphthyridine-2(1H)-one-4-olate.12. A naphthyridine derivative according to claim 1, which is1-benzyl-3-[methyl-3-(3,4,5-trimethoxyphenoxy)propylsulfonium]-1,8-naphthyridine-2(1H)-one-4-olate.13. A pharmaceutical composition comprising a naphthyridine derivativeof claim 1 and a pharmaceutically acceptable carrier.
 14. Apharmaceutical composition according to claim 13, which is an analgesic.15. A pharmaceutical composition according to claim 13, which is adiabetic neuropathy treating agent.
 16. A pharmaceutical compositionaccording to claim 13, which is an adenosine enhancement agent.
 17. Amethod for relieving pain comprising administering an effective amountof a naphthyridine derivative of claim 1 to a patient in need oftreatment.
 18. A method for treating diabetic neuropathy comprisingadministering an effective amount of a naphthyridine derivative of claim1 to a patient in need of treatment.
 19. A method for enhancingadenosine comprising administering an effective amount of anaphthyridine derivative of claim 1 to a patient in need of treatment.20. Use of a naphthyridine derivative of claim 1 for producing apharmaceutical composition for relieving pain.
 21. Use of anaphthyridine derivative of claim 1 for producing a pharmaceuticalcomposition for treating diabetic neuropathy.
 22. Use of a naphthyridinederivative of claim 1 for producing a pharmaceutical composition forenhancing adenosine.